Phase 1 pharmacokinetic and safety study of soticlestat in participants with mild or moderate hepatic impairment or normal hepatic function

Abstract This phase 1, open‐label, three‐arm study (NCT05098054) compared the pharmacokinetics and safety of soticlestat (TAK‐935) in participants with hepatic impairment. Participants aged ≥18 to <75 years had moderate (Child‐Pugh B) or mild (Child‐Pugh A) hepatic impairment or normal hepatic function (matched to hepatic‐impaired participants by sex, age, and body mass index). Soticlestat was administered as a single oral 300 mg dose. Pharmacokinetic parameters of soticlestat and its metabolites TAK‐935‐G (M3) and M‐I were assessed and compared by group. The incidence of treatment‐emergent adverse events (TEAEs) and other safety parameters were also monitored. The pharmacokinetic analyses comprised 35 participants. Participants with moderate hepatic impairment had lower proportions of bound and higher proportions of unbound soticlestat than participants with mild hepatic impairment and normal hepatic function. Total plasma soticlestat pharmacokinetic parameters (maximum observed concentration [C max], area under the concentration‐time curve from time 0 to time of last quantifiable concentration [AUClast], and AUC from time 0 to infinity [AUC∞]) were approximately 115%, 216%, and 199% higher with moderate and approximately 45%, 35%, and 30% higher with mild hepatic impairment, respectively, than healthy matched participants. Moderate hepatic impairment decreased the liver's ability to metabolize soticlestat to M‐I; glucuronidation to M3 was also affected. Mild hepatic impairment resulted in a lower total plasma M‐I exposure, but glucuronidation was unaffected. TEAEs were similar across study arms, mild, and no new safety findings were observed. A soticlestat dose reduction is required for individuals with moderate but not mild hepatic impairment.


| INTRODUC TI ON
Epilepsy syndromes are characterized by specific clinical and electroencephalogram features.One subgroup of epilepsy syndromes are those associated with development and/or epileptic encephalopathy (DEE) or progressive neurologic deterioration. 1 Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are both classified as DEE. 1 DS is characterized by treatment-resistant seizures and neurodevelopmental problems that start in infancy. 2 LGS is associated with the onset of severe treatment-resistant seizures in childhood as well as intellectual disability. 3Currently, DS and LGS are treated with generic antiseizure medications, with some adjunct therapies specifically licensed for DS and LGS, such as fenfluramine and cannabidiol, as well as several generic antiseizure medications. 4,5However, seizure control remains a challenge.Soticlestat (TAK-935) is a novel inhibitor of cholesterol 24-hydroxylase (CH24H) 6 in phase 3 development as an add-on therapy for the treatment of seizures associated with DS and LGS. 7,8olesterol 24-hydroxylase is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol, the latter being implicated as an endogenous modulator of N-methyl-D-aspartate receptors that regulate excitatory synaptic function in the central nervous system as well as neuroinflammation. 6,9,10[13][14][15] Phase 1 studies in healthy volunteers established the pharmacokinetics and pharmacodynamics of soticlestat after single (up to 1350 mg) and multiple doses (100-600 mg/day). 16,17The mean plasma maximum concentration of soticlestat (C max ) was 43.5-7950 ng/mL, median time to C max was 0.250-0.520h, and terminal elimination half-life was 0.820-7.16h across doses ranging from 15 to 1350 mg. 16In these studies, all treatment-emergent adverse events (TEAEs) associated with doses of up to 1350 mg as a single dose and 100-400 mg/day were mild or moderate, and dose dependently reduced plasma 24S-hydroxycholesterol concentrations. 16,17del-based simulations using available data determined 100-300 mg twice daily as the potential dose for phase 2 trials. 18In subsequent phase 1b/2a and phase 2 studies, participants with DEE, cyclin-dependent kinase-like 5 deficiency disorder, DS, or LGS had a reduction in seizure frequency.[21] In vitro, plasma protein binding of soticlestat in humans was concentration-dependent, ranging from 70.6% at 10 μg/mL, 93.4% at 1 μg/mL, and 94.0% at 0.1 μg/mL; soticlestat was mainly bound to human α-1-acid glycoprotein instead of human serum albumin.
In urine, 85.9%, 0.1%, and 0.6% of the administered dose were recovered as TAK-935-G (M3), soticlestat, and metabolite M-I, respectively. 22Soticlestat is predominantly metabolized by the liver via the glucuronidation pathway, 16 with TAK-935-G (M3) being the major metabolite and M-I being the N-oxide metabolite. 18,22Because hepatic impairment can affect the clearance of drugs metabolized by the liver, 23 a pharmacokinetic study in individuals with hepatic impairment is recommended by the US Food and Drug Administration if hepatic metabolism and/or excretion account for a substantial portion (>20% of the absorbed drug) of elimination of the parent drug or active metabolite. 24This study aimed to assess the impact of hepatic impairment on the pharmacokinetics of a single dose of soticlestat and its metabolites M-I and M3.

| Study oversight
All study documents were reviewed by the Advarra Institutional Review Board (Columbia, MD, USA) prior to study initiation.The study was approved by the local institutional review boards of the study sites and conducted in accordance with the Declaration of

Helsinki, International Conference on Harmonization Harmonized
Tripartite Guideline for Good Clinical Practice, and all applicable regulations.All participants provided written informed consent.
Screening occurred at an outpatient visit up to 28 days before dosing.Participants were admitted to the clinic the day before were similar across study arms, mild, and no new safety findings were observed.
A soticlestat dose reduction is required for individuals with moderate but not mild hepatic impairment.

K E Y W O R D S
hepatic function, hepatic impairment, pharmacokinetics, safety, soticlestat, TAK-935 dosing and remained until day 7. Follow-up phone contact occurred 14 ± 2 days after dosing.
The inclusion criteria for all participants were age ≥ 18 to <75 years at screening; body mass index (BMI) ≥18.0 and ≤40.0 kg/ m 2 at screening and ≥50% of participants were required to have a BMI ≥18.0 and ≤35.0 kg/m 2 ; sufficiently healthy for study participation based upon medical history, physical examination, vital signs, electrocardiogram (ECG), and screening clinical laboratory profiles, as deemed by the investigators or designees; supine pulse rate ≥40 and ≤99 beats per minute at screening; continuous nonsmoker or moderate smoker (≤10 cigarettes per day or the equivalent) before screening (participant agreed to consume no more than five cigarettes or equivalent per day from the 7 days prior to check-in and until discharge); and agreement to comply with protocol contraceptive requirements.
For the hepatic impairment arms, additional inclusion criteria were supine blood pressure (BP) ≥80/40 (asymptomatic) and ≤150/95 mmHg at screening; QT interval corrected for heart rate using Fridericia's formula (QTcF) ≤500 ms and ECG findings considered normal or not clinically significant by the investigators or designees at screening; chronic hepatic impairment for ≥3 months before screening that was stable (no significant changes in hepatic function in the 30 days preceding screening or since the last visit if within 6 months before screening) and treated with stable doses of medication; and adequate renal function (creatinine clearance ≥50 mL/min) at screening.To assess hepatic impairment, two hepatic function assessments ≥48 h apart were required during the screening period unless a Child-Pugh assessment score within 3 months prior to screening was available, in which case one assessment was conducted during screening.If the Child-Pugh scores from both assessments indicated the same liver function category, soticlestat was administered as scheduled.If the results differed, a third assessment was conducted ≥24 h after the second.If the results of the second and third assessments agreed regarding the participant's liver function category, the participant was enrolled and received the day 1 dose within 48 h of the third assessment.If the second and third measurements differed, the participant was not eligible for the study.
Healthy participants were matched to hepatic-impaired participants by sex (±2 per sex), age (mean ± 10 years), and BMI (mean ± 10%).In addition, healthy participants needed to have supine BP ≥90/40 and ≤150/95 mmHg at screening; QTcF ≤450 (males) or ≤470 ms (females) and ECG findings considered normal or not clinically significant by the investigators or designees at screening; liver function tests including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin at or below the upper limit of normal at screening and check-in; and adequate renal function (creatinine clearance ≥60 mL/min) at screening.
The exclusion criteria for the study included history or presence of a clinically significant medical or psychiatric condition or disease (aside from hepatic impairment in the appropriate arms) or presence of psychotic disorders such as psychosis, delusions, or schizophrenia in the opinion of the investigators or designees; history of liver or other solid organ transplant (hepatic impairment arms); history or presence of alcoholism and drug abuse within the past 6 months (hepatic impairment) or 2 years (healthy participants) prior to dosing; positive result at screening for human immunodeficiency virus; positive result at screening for hepatitis B surface antigen or hepatitis C virus (HCV; healthy participants); positive for hepatitis B surface antigen with hepatitis B virus DNA ≥1000 copies/mL in the plasma (hepatic impairment); and positive for HCV antibodies with detectable HCV RNA in the plasma (hepatic impairment).
The moderate hepatic impairment arm was conducted first, followed by the matched normal hepatic function arm.After enrollment of the mild hepatic impairment arm, up to 12 additional participants could be enrolled for the matched normal hepatic function group to ensure a minimum of 12 participants with normal hepatic function and matching the mean of the mild hepatic impairment arm by age, sex, and BMI.Soticlestat was taken as three 100 mg immediaterelease tablets on day 1 with approximately 240 mL water under fasting conditions (≥10 h before dosing and 4 h post-dose).

| Study assessments and endpoints
Medical history and demographic data were recorded at screening.Twelve-lead ECG, pulse rate, and BP were taken 2, 24, and 144 h after dosing or at early termination, and respiratory rate and temperature were taken 24 and 144 h after dosing or at early termination.Hematology, coagulation, serum chemistry, and urine analysis were conducted 48 and 144 h after dosing or at early termination.

| Statistical methods
Descriptive statistics were derived for the concentration data: number of observations (n), arithmetic mean (mean), standard deviation (SD), arithmetic percent coefficient of variation (CV%), standard error of the mean, minimum, median, and maximum.
Pharmacokinetic parameter data for total plasma soticlestat, M-I, and M3, and unbound plasma soticlestat were summarized by hepatic function arm using n, mean, SD, CV%, standard error of the mean, minimum, median, maximum, geometric mean (C max and AUCs only), and geometric CV% (C max and AUCs only).Continuous variables were summarized using n, mean, SD, minimum, median, and maximum.Analysis of variance was used to compare hepatic function groups, and all statistical analyses were conducted using SAS ® version 9.4.

| Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to corresponding entries in http:// www.guide topha rmaco logy.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY, 26 and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20. 26,27| RE SULTS

| Study population
The study was conducted at four centers in the United States between 29 October 2021 and 7 June 2022.Thirty-six participants were enrolled and completed the study, and their demographics are shown in Table 1.The moderate hepatic impairment arm (n = 8) was enrolled first followed by 12 participants with normal hepatic function who were matched to the moderate hepatic impairment arm by age, sex, and BMI.After a preliminary data analysis that estimated the effect of moderate hepatic impairment on soticlestat pharmacokinetics, the mild hepatic impairment arm was enrolled.Among the 12 previously enrolled healthy participants, five also matched to the mild hepatic impairment arm, while the remaining seven participants could not be used for matching purposes to this group.
As a result, seven additional healthy participants were enrolled to ensure a minimum of 12 participants with normal hepatic function and matching the mean of the mild hepatic impairment arm by age (mean ± 10 years), sex (± 2 per sex), and BMI (mean ± 10%) were enrolled.One participant was enrolled with moderate hepatic impairment at screening but was determined to have severe hepatic impairment the day before dosing.This participant was dosed and followed through the study, but their data were not included in the pharmacokinetic analyses.
A preliminary pharmacokinetic data analysis demonstrated an approximately 3-fold increase in soticlestat total plasma exposure in participants with moderate hepatic impairment compared with healthy matched participants with normal hepatic function.Based on this information, a decision was taken not to recommend soticlestat dosing in patients with severe hepatic impairment.The protocol was amended and participants with severe hepatic impairment were not enrolled in the current study; instead, the impact of soticlestat was assessed in participants with mild hepatic impairment.

| Pharmacokinetic parameters: soticlestat
Participants with moderate hepatic impairment had lower proportions of bound soticlestat and higher proportions of unbound soticlestat than participants with mild hepatic impairment and agematched participants with normal hepatic function.Bound and unbound soticlestat values were similar between participants with mild hepatic function and their matched participants with normal hepatic function (Table S1).Both total and unbound plasma soticlestat concentrations showed a multiphasic disposition (Figure 1; Figure S1).

F I G U R E 1
Mean plasma concentrations (semi-log scale) of (A) total soticlestat, (B) unbound soticlestat, (C) total M-I, and (D) total M3.HI, hepatic impairment.

| Safety
Five participants experienced a total of six TEAEs, as shown in 6.All TEAEs were mild and had resolved by the end of the study, and two were considered to be study drug related.There were no TEAEs based on serum chemistry, hematology, coagulation, urinalysis, vital signs, ECG, or Columbia-Suicide Severity Rating Scale.

| DISCUSS ION
The liver is involved in the clearance of many medications, and hepatic impairment can reduce the liver's metabolic capacity through altered physiological parameters such as a decreased abundance of drug-metabolizing enzymes, decreased functional hepatic volume, decreased hepatic blood flow, and decreased drug-binding plasma TA B L E 2 Pharmacokinetic parameters for total and unbound plasma soticlestat.Abbreviations: AUC ∞ , area under the total plasma concentration-time curve from time 0 to infinity; AUC last , area under the total plasma concentration-time curve from time 0 to time of the last quantifiable total plasma concentration; CL/F, apparent clearance after extravascular administration, calculated using the observed value of the last quantifiable total plasma concentration; C max , maximum observed total plasma concentration; SD, standard deviation; t ½z , terminal disposition phase half-life; t max , time of first occurrence of maximum observed total plasma concentration; V Z /F, apparent volume of distribution during the terminal disposition phase after extravascular administration, calculated using the observed value of the last quantifiable total plasma concentration.
proteins.For drugs primarily metabolized by the liver, hepatic impairment can lead to decreased clearance and increased exposure.
9][30][31] Metabolism is the main elimination pathway for soticlestat, 22 and therefore this study was conducted to evaluate the impact of hepatic impairment on soticlestat pharmacokinetics to inform dosing decisions in patients with hepatic impairment.A preliminary physiology-based pharmacokinetic model and simulation predicted a <50% decrease in CL/F in all the hepatic impairment groups (mild, moderate, and severe) versus the group with normal hepatic function.Based on the model predictions, the pharmacokinetics of total plasma soticlestat in participants with moderate hepatic impairment and healthy matched participants with normal hepatic function were assessed first, and a preliminary analysis was conducted. 24However, the preliminary model predictions underestimated the impact of moderate hepatic impairment on soticlestat plasma exposure, likely because some of the model input parameters, such as the faction of soticlestat metabolized by each metabolic enzyme, were not available at the time of the analysis.The preliminary analysis indicated a higher impact of moderate hepatic impairment on total plasma soticlestat than predicted, with AUC ∞ and AUC last values approximately 3-fold higher compared with healthy participants with normal hepatic function.
As a result, a decision was made not to recommend soticlestat administration in patients with severe hepatic impairment, and participants with severe hepatic impairment were not included in the study.Instead, the impact of mild hepatic impairment on the pharmacokinetics of soticlestat was investigated.
The pharmacokinetic parameters of soticlestat in individuals with normal hepatic function were similar to those reported in other soticlestat phase 1 studies of healthy persons, 16,17,32  Abbreviations: AUC ∞ , area under the total plasma concentration-time curve from time 0 to infinity; AUC last , area under the total plasma concentration-time curve from time 0 to time of the last quantifiable total plasma concentration; CI, confidence interval; C max , maximum observed total plasma concentration; CV%, arithmetic percent coefficient of variation; GMR, geometric least squares mean ratio; LSM, least squares mean.
matched participants with normal hepatic function.As introduced earlier, soticlestat was mainly bound to human α-1-acid glycoprotein.
Decreased α-1-acid glycoprotein levels have been observed in patients with liver cirrhosis compared with healthy controls.4][35][36] As expected, moderate hepatic impairment caused decreased binding of soticlestat to plasma proteins compared with healthy matched participants (unbound fraction: 17.5% vs. 9.68%, respectively) and had an even greater impact on unbound plasma soticlestat exposure.Mild hepatic impairment had a negligible impact on protein binding (unbound fraction: 7.99% vs. 9.36%, respectively) resulting in similar unbound plasma soticlestat exposure to that of participants with normal hepatic function.
As discussed earlier, for drugs such as soticlestat that are pri- Abbreviations: AUC ∞ , area under the total plasma concentration-time curve from time 0 to infinity; AUC last , area under the total plasma concentration-time curve from time 0 to time of the last quantifiable total plasma concentration; CI, confidence interval; C max , maximum observed total plasma concentration; CV%, arithmetic percent coefficient of variation; GMR, geometric least squares mean ratio; LSM, least squares mean; MPR, metabolite-to-parent ratio.
would decrease the liver's ability to metabolize soticlestat to metabolites.Mild hepatic impairment only had an impact on M-I and not on glucuronidation of soticlestat via UGT2B4 and UGT1A9; the lack of impact on glucuronidation may be due to the large UGT capacity in the liver.
The metabolites (M-I and M3) were measured in this study to gain an estimate of the effect of hepatic impairment on the liver's ability to metabolize soticlestat to these metabolites.However, any impact on the exposure of these metabolites is not clinically relevant; the M-I metabolite displayed only weak CH24H inhibition that was 203-fold lower than for soticlestat (IC 50 : 913.5 nmol/L for M-I; 4.5 nmol/L for soticlestat) while the M3 metabolite is inactive.As such, the assessment of dose adjustment will be based solely on the plasma exposure to the parent drug, soticlestat.
TEAEs were similar across the study arms, all were mild, and no new safety findings were observed in the study.Abbreviations: AUC ∞ , area under the total plasma concentration-time curve from time 0 to infinity; AUC last , area under the total plasma concentration-time curve from time 0 to time of the last quantifiable total plasma concentration; CI, confidence interval; C max , maximum observed total plasma concentration; CV%, arithmetic percent coefficient of variation; GMR, geometric least squares mean ratio; LSM, least squares mean; MPR, metabolite-to-parent ratio.

TA B L E 6
Treatment-emergent adverse events.
5 and 10 h after dose administration.TEAE monitoring occurred throughout the study and at follow-up.The study's primary endpoints were the following pharmacokinetic parameters for soticlestat: C max ; area under the total plasma concentration-time curve from time 0 to infinity (AUC ∞ ); and AUC from time 0 to time of the last quantifiable total plasma concentration (AUC last ).The incidences of TEAEs and clinically significant abnormal values for laboratory evaluations, vital signs, ECG parameters, and Columbia-Suicide Severity Rating Scale were secondary objectives.Exploratory endpoints were plasma pharmacokinetic parameters of soticlestat metabolites M-I and M3 (C max , AUC ∞ , AUC last , metabolite-to-parent ratio [MPR] C max , MPR AUC last , and MPR AUC ∞ ); additional plasma pharmacokinetic parameters of soticlestat and the metabolites M-I and M3 (time of first occurrence of C max [t max ] and terminal disposition phase half-life [t ½z ]); additional plasma pharmacokinetic parameters of soticlestat (apparent clearance after extravascular administration, calculated using the observed value of the last quantifiable total plasma concentration [CL/F]; apparent volume of distribution during the terminal disposition phase after extravascular administration, calculated using the observed value of the last quantifiable total plasma concentration [Vz/F]); and plasma protein binding of soticlestat: fraction of unbound soticlestat.Total soticlestat, M-I, and M3 concentrations and unbound soticlestat concentrations were determined using liquid chromatography-tandem mass spectrometry by CMIC, Inc. (Hoffman Estates, IL, USA).Unbound plasma soticlestat concentrations were measured using ultrafiltration (by CMIC, Inc.).Pharmacokinetic parameters were calculated using Phoenix ® WinNonlin ® version 8.3.4.
Total plasma soticlestat was quantifiable by 0.133 h post-dose in most participants with moderate or mild hepatic impairment, and by 0.25 and 0.133 h post-dose in most participants with normal hepatic function matched to the moderate and mild hepatic impairment groups, respectively.Pharmacokinetic parameters for total and unbound plasma soticlestat are shown in Abbreviations: BMI, body mass index; SD, standard deviation.a Total = 17.
Comparison of total plasma M3 in participants with moderate hepatic impairment versus matched participants with normal hepatic function resulted in GMRs of 49.89% for C max , 86.80% for AUC last , and 86.88%, for AUC ∞ .The corresponding GMRs for mild hepatic impairment versus matched participants with normal hepatic function were 104.26%, 105.31%, and 105.34%, respectively (Table5; TableS3).GMRs of MPRs for C max , AUC last , and AUC ∞ were 23.21%, 27.45%, and 28.57%, respectively, for moderate hepatic function and 71.70%, 77.86%, and 84.96%, respectively, for mild hepatic function versus normal hepatic function.

Hepatic impairment Controls with normal hepatic function matched to each hepatic impairment group Moderate (n = 8) Mild (n = 8) Moderate (n = 12) Mild (n = 12)
Comparison of pharmacokinetic parameters for total and unbound plasma soticlestat in participants with moderate and mild hepatic impairment versus matched controls with normal hepatic function.
∞ , 1925 vs. 1182 ng•h/mL).Total plasma soticlestat PK parameters (primary endpoints; C max , AUC last , and AUC ∞ ) were approximately 115%, 216%, and 199% higher with moderate hepatic impairment and approximately 45%, 35%, and 30% higher with mild hepatic impairment, respectively, than healthy TA B L E 3 Comparison of pharmacokinetic parameters for total plasma M-I in participants with moderate and mild hepatic impairment versus matched controls with normal hepatic function.
18,221A9 and UGT2B4, with these enzymes accounting for approximately 90% of soticlestat metabolism.The N-oxide metabolite (M-I) is formed by CYP3A4.18,22Considering the metabolic pathway, as discussed earlier, it was expected that moderate hepatic impairment TA B L E 4 Comparison of pharmacokinetic parameters for total plasma M3 in participants with moderate and mild hepatic impairment versus matched controls with normal hepatic function.
TA B L E 5